PROJECT SUMMARY The overall goal of this proposal is to develop and evaluate a multi-parametric set of quantitative MRI (qMRI) tools for monitoring the microstructural changes associated with traumatic peripheral nerve injury (TPNI) and subsequent surgical repair. Up to 5% of all admissions to level I trauma centers have a TPNI; and a significant increase in the incidence of TPNI has been noted in recent military missions. Common etiologies include trauma to limbs from penetrating injury, crush, stretch, and ischemia. Clinical management of TPNI faces two limitations: i) the inability to acutely identify injuries that require surgery (e.g., nerve lacerations) and ii) the inability to detect failed nerve surgeries prior to muscle re-innervation?may take months or years depending on the injury site. Due to these limitations, physicians are required to a ?wait and watch? using qualitative measures obtained from patient history and physical exam. This results in delayed management and increased instances of permanent motor/sensory loss. Quantitative MRI (qMRI) techniques may provide a non-invasive, quantitative characterization of nerve microstructure in vivo following trauma and throughout the recovery process (i.e., prior to muscle re-innervation). We propose to develop and evaluate qMRI techniques for this purpose. If successful, these strategies could improve outcomes by i) identifying patients that require surgery and ii) identifying surgical failures earlier than current techniques, even guiding re-operation. The proposed qMRI methods will be developed and evaluated as potential biomarkers of nerve recovery via human studies in the median/ulnar nerves of the forearm and wrist. We will first develop and optimize qMRI methods of these nerves (Aim 1). MRI of peripheral nerves is challenging due a number of factors, including the need for fast, high-resolution imaging and the influence of fat. The PI has previously shown success in developing and optimizing qMRI methods to evaluate inherited neuropathies. Here, we will build upon these previous developments and employ quantitative magnetization transfer and diffusion imaging to assay Wallerian degeneration and axonal outgrowth following injury/repair, respectively. We have shown that inflammation confounds diffusion-based assessments of nerve recovery in a rat model of trauma. As a result, we will also evaluate models the account for the influence of inflammation. Once optimized, we will perform cross-sectional studies (Aim 2) in patients with nerve injuries of varying severity to evaluate the ability of qMRI to identify injuries that require surgery. We will also perform longitudinal studies (Aim 3) following surgery to evaluate the ability of qMRI to monitor nerve regeneration, with results compared to EMG/NCS and function (e.g., grip strength). Finally, we will explore MRI methods to monitor the downstream effects of TPNI on skeletal muscle, as this information may improve future revisional surgery recommendations when failed repairs are detected. Specifically, we will measure T2/fat-fraction (reports on acute/chronic denervation) in muscles innervated by the median/ulnar nerves (e.g., muscles of the hand) to assess their viability after nerve repair.